Induction of heme-oxygenase 1 inhibits endothelial cell activation by endotoxin and oxidant stress.
Induction of heme-oxygenase 1 inhibits endothelial cell activation by endotoxin and oxidant stress.
复制标题
血红素加氧酶 1 的诱导可抑制内毒素和氧化应激引起的内皮细胞活化。
DOI：
10.1067/msy.2003.215
复制
发表时间：
2003
期刊：
影响因子：
3.8
通讯作者：
Maier,RonaldV
中科院分区：
文献类型：
--
作者：
Bulger,EileenM;Garcia,Iris;Maier,RonaldV
背景氧化应激增加与许多疾病状态有关，包括缺血/再灌注损伤或脓毒症引起的全身炎症。我们以前已经证明，氧化剂增强促炎症反应的内毒素（脂多糖），虽然抗氧化剂抑制这种反应。血红素加氧酶1（HO-1）是一种诱导型细胞保护酶，在氧化应激条件下上调。方法用氯化血红素（100 μ mol/L）预处理人脐静脉内皮细胞5h，Western blot检测HO-1蛋白的表达。在氯化血红素暴露后，用二酰胺、丁氨酰亚砜亚胺、黄嘌呤氧化酶或葡萄糖氧化酶处理细胞1小时以诱导氧化应激或用脂多糖处理细胞以诱导炎症反应。白细胞介素8（IL-8）和前列腺素I2（PGI2）的生产进行了测定，酶联免疫吸附试验; p38激酶，p42/44细胞外调节激酶，和c-jun N末端激酶的活化测定通过Western blot. ResultsHO-1蛋白增加3倍，暴露于氯化血红素在所有条件下。IL-8的产生响应脂多糖和黄嘌呤氧化酶显着抑制氯化血红素暴露，虽然PGI2的生产没有受到影响。HO-1蛋白水平的上调导致对脂多糖和氧化剂诱导的所有3种促分裂原活化蛋白激酶的活化的抑制：p38激酶、p42/44细胞外调节激酶和c-jun N末端激酶。结论氯化血红素诱导HO-1可抑制内皮细胞的促炎反应，如抑制IL-8产生而不影响PGI2产生所证明的。所有3个丝裂原活化蛋白激酶信号级联都受到影响，这表明这种作用的机制可能与细胞信号转导过程有关。（Surgery 2003; 134：146 - 152.）
BackgroundIncreased oxidant stress has been implicated in a number of disease states, including systemic inflammation caused by ischemia/reperfusion injury or sepsis. We have demonstrated previously that oxidants enhance the proinflammatory response to endotoxin (lipopolysaccharide), although antioxidants inhibit this response. Heme-oxygenase 1 (HO-1) is an inducible, cytoprotective enzyme, which is up-regulated under conditions of oxidant stress. We hypothesized that the induction of HO-1 protein would attenuate the proinflammatory response of endothelial cells to lipopolysaccharide and oxidant stress.MethodsHuman umbilical vein endothelial cells were pretreated with hemin (100 μmol/L) for 5 hours, and the induction of HO-1 was confirmed by Western blot. After hemin exposure, cells were treated for 1 hour with either diamide, buthione sulfoximine, xanthine oxidase, or glucose oxidase to induce oxidant stress or lipopolysaccharide to induce an inflammatory response. Interleukin 8 (IL-8) and prostaglandin I2(PGI2) production were measured by enzyme-linked immunosorbent assay; p38 kinase, p42/44 extracellular regulated kinase, and c-jun N terminal kinase activation were measured by Western blot.ResultsHO-1 protein was increased 3-fold by exposure to hemin under all conditions. IL-8 production in response to lipopolysaccharide and xanthine oxidase was inhibited significantly by hemin exposure, although PGI2production was not affected. The up-regulation of HO-1 protein levels resulted in the inhibition of the lipopolysaccharide- and oxidant-induced activation of all 3 mitogen-activated protein kinases: p38 kinase, p42/44 extracellular regulated kinase, and c-jun N terminal kinase.ConclusionThe induction of HO-1 by hemin results in inhibition of the proinflammatory response of endothelial cells, as evidenced by the inhibition of IL-8 production without affecting PGI2production. All 3 mitogen-activated protein kinase signaling cascades are affected, which suggests that the mechanism of this effect may be proximal in the cell signaling process. (Surgery 2003;134:146-52.)